tbuckley/cabot-search huggingface dataset:
Soluble urokinase-type plasminogen activator receptor, suPAR, as a prognostic biomarker in advanced pancreatic cancer.
Authors: Rikke Løvendahl Eefsen, Ib Jarle Christensen, Dan Calatyud, Astrid Zedlitz Johansen, Inna Markovna Chen, Louise Skau Rasmussen, Per Pfeiffer, Niels Henrik Hollander, Fahimeh Andersen, Julia S. Johansen, Gunilla Hoyer-Hansen
Journal: Journal of Clinical Oncology (2023)

e16277 Background: High levels of intact and cleaved forms of the urokinase-type Plasminogen Activator Receptor (uPAR) in tissue and blood are associated with a poor prognosis in several types of cancer, including lung, colon, bladder, and cholangiocarcinoma. The soluble forms of uPAR (suPAR) have not been investigated in patients with pancreatic ductal adenocarcinoma (PDAC). The aim was to determine if circulating levels of intact and cleaved suPAR were associated with overall survival (OS) in patients with advanced PDAC. Methods: Patients with PDAC stage 3 or 4 were consecutively included in the BIOPAC study (ClinicalTrials.gov ID: NCT03311776) in a training cohort (n = 230, age 45-89 years, 56% females) from Herlev Hospital and a validation cohort (n = 115, age 40-82 years, 59% females) from four other Danish hospitals between 2008 to 2014. A total of 95% of the patients in the training cohort and 93% in the validation cohort received first-line palliative chemotherapy. One patient was alive at the time of analysis at 8 years follow-up. Serum samples were collected prior to palliative chemotherapy. Different suPAR forms were determined using time-resolved fluorescence immunoassays (TR-FIA). The Cox proportional hazards model was used for uni- and multivariate analyses. Age, performance status, stage (4 vs 3), gender, Charlson age-adjusted comorbidity index, and CA19-9 were included in the multivariate analysis for OS. Results: In the training cohort, high level of suPAR domain I was an independent biomarker of short OS (HR, 1.37, 95% CI 1.15-1.63, p = 0.0004). High CA19-9 (HR, 1.08, 95% CI 1.04-1.12, p &lt; 0.0001), PS, and stage were also independent prognostic parameters in the training cohort. In the validation cohort, high level of suPAR domain I (HR, 1.91, 95% CI 1.36-2.69, p = 0.0002) and CA 19-9 (HR, 1.09, 95% CI 1.01-1.17, p = 0.02) were confirmed as independent prognostic biomarkers for short OS. No correlation was observed between suPAR domain 1 and CA19-9 (r = 0.059, p = 0.21). Conclusions: A high pretreatment circulating level of suPAR domain I is associated with a short OS in patients with advanced PDAC, and the biomarker is independent of CA19-9. The results warrant further investigation of suPAR domain 1 as a biomarker in patients with PDAC.
Association of emotional support with quality of life, mental health, and survival among older adults with gastrointestinal (GI) malignancies.
Authors: Daniel Clausing, Mackenzie Elisha Fowler, Christian Harmon, Darryl Alan Outlaw, Mehmet Akce, Bassel F. El-Rayes, Smith Giri, Grant Richard Williams
Journal: Journal of Clinical Oncology (2023)

12050 Background: Emotional support (ES) is the most frequently reported support need among older adults with cancer. Yet, the association of ES with cancer outcomes is largely unknown. This study examined the association of ES with health-related quality of life (HRQoL), mental health, and survival among older adults with GI malignancies. Methods: We included older adults (≥60y) newly diagnosed with GI cancer and undergoing a self-reported geriatric assessment (GA) at first clinic visit. Self-reported ES, measured by the Medical Outcomes Survey was the primary exposure. Outcomes included physical and mental HRQoL as measured by the Patient-Reported Outcomes Measurement Information System® (PROMIS) 10-item global assessment, anxiety and depression as measured by the PROMIS Anxiety and Depression Short Form 4a, respectively, and one-year, two-year, and overall survival. Linear regression evaluated the association between ES and t-scores of physical/mental HRQoL. Logistic regression evaluated the association of ES with anxiety and depression. Models were adjusted for age, race, sex, and cancer type/stage. Kaplan-Meier curves and log-rank tests evaluated the association between ES and survival outcomes. Results: Overall, 795 participants were included. The median age was 68 (IQR: 64-74) and patients were 58.0% male, and 74.6% White. The most common cancers included colorectal (37.9%) and pancreatic (30.8%), with mostly advanced staged disease (Stage III/IV: 72.1%). A majority (77.6%) had adequate ES. Patients with inadequate ES were more likely to be Black (31.5 vs. 20.8%, p=0.005), disabled (24.1 vs. 10.4%, p&lt;0.001), and widowed/divorced (54.2 vs. 24.8%, p&lt;0.001). After adjustment, patients with inadequate ES had lower physical and mental HRQoL t-scores (Physical β: -3.35, 95% CI: -5.25, -1.46; Mental β: -2.46, 95% CI: -4.11, -0.81) and higher odds of depression (aOR: 2.22, CI: 1.34-3.69). There was no statistically significant association with anxiety (aOR:1.15, CI: 0.73, 1.81). No differences were observed between patients with inadequate versus adequate ES in one-year, two-year, or overall survival (Log-Rank tests: one-year, p=0.952; two-year, p=0.606; overall, p=0.584). Conclusions: Older adults with inadequate ES have higher odds of poor physical and mental HRQoL and depression, but no difference in survival compared to those with adequate ES. Further work is necessary to determine if interventions to improve ES also improve HRQoL and depression.
Diffuse large B-cell lymphoma in HHV8+ multicentric castleman disease: A national analysis of demographic features.
Authors: Maximillian Whooley, Darby Keirns, Xinxin Wu, Andrew Luker, Peter T. Silberstein, Beau Hsia
Journal: Journal of Clinical Oncology (2023)

e19535 Background: Diffuse large B-cell lymphoma (DLBCL) in human herpesvirus 8 associated (HHV8+) multicentric Castleman disease (MCD) is a rare type of DLBCL. DLBCL, the most common non-Hodgkin lymphoma, is a cancer arising in the lymphatics. HHV8+ MCD is a lymphoproliferative disorder usually occurring in HIV patients. Patients who develop DLBCL in this setting typically die within a year. Prior National Cancer Database (NCDB) studies have assessed survival and demographics in the broader category of CD20- LBCLs, but have not specifically examined the socioeconomic and demographics associated with DLBCL in HHV8+ MCD. Methods: A retrospective analysis of NCDB data from 2010 – 2020 included patients diagnosed with DLBCL in HHV8+ MCD (N = 237). Demographic factors such as sex, race, Hispanic ethnicity, income status, insurance status, Charlson-Deyo score, facility type/location, and metastasis at diagnosis were evaluated with descriptive statistics. Primary site was also examined. Incidence trends were assessed via regression analysis. Results: A total of 237 patients with DLBCL in HHV8+ MCD were identified in the database, with an average incidence of 21.5 cases per year (R2 = 0.236, SD = 5.7, range = 9 – 29). 74.7% were male and the average age of diagnosis was 53.8 years (SD = 18.62, range = 3 – 90). 40 different primary sites were identified, with the most common being lymph nodes of multiple regions (32.9%). Extranodal primary sites were rare but documented. Charlson-Deyo comorbidity scores varied: Score 0 = 61.6%, Score 1 = 8.4%, Score 2 = 4.2%, Score ≥ 3 = 25.7%. Incidence for race was highest among Whites (69.2%), followed by Blacks (25.3%), then Asians (3.4%). 8.4% of patients were of Hispanic ethnicity. A greater percentage of patients were in the top income quartile (33.8%), compared to the second (19.7%), third (23.9%), and fourth (22.5%). Most patients were either insured privately or by Medicare (73.9%), whereas 8.9% were uninsured. Most were treated at academic facilities (54.7%), and many were treated at facilities in the Eastern United States (47.5%). 19.1% of patients had metastases at diagnosis, most often in distant lymph nodes (6.1%). Conclusions: This study provides insight into the demographics of patients diagnosed with DLBCL in HHV8+ MCD. This cancer showed a nearly 3-fold male preponderance and primarily affected Whites, mirroring existing trends in DLBCL overall. About one fifth of patients presented with metastasis at diagnosis. Interestingly, patient Charlson-Deyo scores displayed a bimodal distribution, with 87.3% of patients having a Score of either 0 or ≥3. The top income quartile was most affected, but patients were more evenly distributed among the bottom three. Further investigation is needed to better define the role of demographics in shaping diagnostic, therapeutic, and outcome discrepancies in those with DLBCL in HHV8+ MCD.
Real world challenges in defining oligometastatic disease in clinical practice.
Authors: Inmaculada Navarro-Domenech, Aisling S. Barry, Jane Tsai, Grace Ma, Miguel García-Pardo, Ian Hirsch, Philip Wong
Journal: Journal of Clinical Oncology (2023)

e18873 Background: There is little data understanding the multi-disciplinary application of oligo-metastatic disease (OMD) treatment and decision-making. Through an anonymous survey, we sought to understand the knowledge gaps and challenges faced by physicians caring for cancer patients in deciphering and delivering treatments for patients with OMD. Methods: This was an IRB approved single institution quality improvement study conducted via an anonymous electronic survey. Three clinical cases of OMD that ranged from de-novo OMD to oligo-progressive disease, were presented to check participants’ comprehension of OMD. Descriptive statistics were used to summarize quantifiable information obtained from the survey. A qualitative approach was taken for the open-ended questions, in which the answers were reviewed by 2 independent readers and grouped together into common themes, and analyzed using sector and bar diagram, decision-tree method and sorted by prevalence. Results: The survey was answered by 70 clinicians (39 (56%) medical oncologists, 17 (24%) radiation oncologists, 5 (7%) surgeons, 9 (13%) from anatomical pathology/radiology/palliative care). The three clinical cases were correctly answered in 63%, 94% and 76%, respectively; of these, 76% to 84% would offer local treatment for each OMD scenario. Most (79%) perceived differences between local therapies (surgery, SBRT and RFA). Surgery was preferred to improve local control and overall survival, while SBRT was considered as being less invasive and more beneficial to patient quality of life. The definition of OMD was perceived by 94% as patients harboring 1-5 metastases. The main perceived challenges consist of lack of evidence in clinical and prospective trial data. Referrals are hindered as the goals and approach of OMD care are unclear. The most important determinant in deciding whether patients may benefit from OMD treatment is tumor histology and molecular profile. Conclusions: SBRT as a treatment of OMD emerged during an era of rapid expansion in systemic treatments and improvements in imaging techniques. Positive and negative trials in various histologies of cancer further added uncertainty on who would best benefit from OMD SBRT. As more radiation centres offer SBRT, the discordance in the outcome expectations from referring physicians, radiation oncologists and patients will need to be addressed to ensure that patients’ goals of care are met.
CDH12 and the development of the neuronal subtype in MIBC.
Authors: Xingyu Chen, Mukta Basu, Simon Knott, Dan Theodorescu
Journal: Journal of Clinical Oncology (2023)

e16579 Background: We discovered a novel cell epithelial cell population we termed “C3” in muscle-invasive bladder cancer (MIBC) that is negatively prognostic for surgery and chemotherapy. This cell population shares similarities with the neuronal subtype MIBC (NEBC) which has limited treatment options and is driven by unclear molecular mechanisms. The objective of the study was to determine if NEBC is driven by some of the genes that are overexpressed in C3 cells. A top overexpressed and C3 cell specific gene that is also enriched in normal neuronal tissue is Cadherin 12 (N-Cadherin 2, CDH12). Hence, we initiated a study of this gene. Methods: We overexpressed CDH12 in two murine MIBC cell lines (NA13 and MB49) and then inoculated them into mice. Tumor growth kinetics were studied, and single-nucleus RNA sequencing (snRNA-seq) and bulk RNA sequencing were then used to evaluate the tumors. Tissue samples from patients with MIBC were also analyzed using snRNA-seq and Co-detection by Indexing (CODEX) multiplexed immunofluorescence, and our bioinformatics analysis combined transcriptomic profiles from &gt; 2000 MIBC samples from published datasets, to characterize the transcriptional programs induced by enforcing CDH12 expression. Results:Enforced expression of CDH12 led to enhanced tumor growth and the appearance of the neuroendocrine tumor phenotype. NEBC from human samples showed the highest expression of CDH12, and snRNA-seq results showed that NEBC also has the highest proportion of CDH12 epithelial cells and demonstrated co-expression of CDH12 and neuronal markers (NCAM1, CHGA, and SYP). RNA velocity analysis in murine and human tumors implicated CDH12 as a driver for the development of the neuronal subtype. Conclusions: To our knowledge, this study provides the first identification of a genetic driver leading to NEBC and implicates a novel gene, CDH12 in this process.
Reducing infusion center wait times in a resource-limited setting.
Authors: Amy Little Jones, Robyn Cobb, Bryana Anderson, Radhika Kainthla
Journal: Journal of Clinical Oncology (2023)

6567 Background: Time toxicity is increasingly recognized as an important factor in quality of life in cancer patients, and this effect may be amplified in under-resourced oncology settings. In the safety-net oncology center at Parkland Health (PH), wait time from infusion appointment check-in to treatment start was 147 minutes in June 2022, which led to significant patient frustration, delays in care, and staff dissatisfaction. We aimed to decrease wait time by 20% by December 2022. Methods: Baseline wait time data for patients getting infusions in the oncology infusion center was collected daily from the electronic medical record (EMR) time stamps of check in and infusion start (first IV medication given), and the average time was calculated. A value stream map detailing the steps required to start infusion with time stamps was produced. Stakeholders were queried to identify causes of delay, an Ishikawa diagram was constructed, and a priority matrix was developed to determine the most impactful interventions. The first PDSA cycle (July-Oct 2023) intervention consisted of working group formation and implementation of separate infusion pathway for patients getting injections (“fast track”). The second PDSA cycle (Nov-Dec 2023) intervention was rescheduling infusion-only patients to the least congested times of the day to relieve the bottleneck that occurred in the late mornings for patients with labs or provider visit prior to infusion. Patients and infusion center providers were surveyed about their perception of wait times. Results: Average wait times decreased from 147 minutes to 131 minutes during first PDSA cycle, a 10.8% improvement from baseline. From Nov-Dec 2023 during second PDSA cycle, wait time improved to 127 minutes, a 15.7% improvement from baseline. The average daily number of infusions and injections increased from 106/day baseline to 115/day by Dec 2023; an increase of 8.5%. Qualitative surveys of patients and infusion providers endorsed increased satisfaction with infusion process. Conclusions: Using established quality improvement methods, we improved average wait times for Parkland Health oncology infusion patients by 15.7% over a 6 month period. While we did not meet our goal, we increased daily capacity to treat patients by 8.5% while improving overall infusion wait time. We also improved perceptions of quality of care.
Association of CAR-T cell secreting CD47 blocking protein with an enhanced antitumor activity in small cell lung cancer.
Authors: Fuchun Guo, Qizhi Ma, Yongsheng Wang
Journal: Journal of Clinical Oncology (2023)

e20512 Background: Notch ligand family DLL3 has been considered a therapeutic target for small cell lung cancer. CD47/SIRPa is an important immunosuppressive factor in the tumor microenvironment and is considered to be a "checkpoint" of innate immune cells. Here, we described an DLL3 targeting CAR-T cells secreting CD47/SIRPa signal blocking protein. We hypothesized that the armored CAR-T cells, by blocking the CD47/SIRPa signal with specific antibodies may promote macrophages to engulf tumor cells and induce anti-tumor immune response, thus addressing a clinical need of cell therapy in SCLC. Methods: Bioinformatics analysis of immune cell composition in the microenvironment of small cell lung cancer, focusing on macrophage content and phenotypic characteristics. The CAR genes were cloned into the lentiviral vector pWPXLd, the expression, phenotype, activation, proliferation, killing and cytokine release of CAR-T cells were detected by flow cytometry, Western blot, RTCA and ELISA; NSG mice were injected subcutaneously with H446-DLL3 cells or H446-DLL3(+/-) combined with CAR-T cells or armored CAR-T cells. Tumor size was measured every 3rd day. The number and phenotype of macrophages in tumors were detected by FCM. Results: Bioinformatics analysis showed that tumors with high expression of DLL3 were often accompanied by downregulation of antigen presentation-related genes; there is a large amount of macrophage infiltration in SCLC, and the later the stage, the more the infiltration. CAR-T cells co-cultured with target cells could effectively activate T cells, promote CAR-T cell proliferation, secrete IL-2, IFN-γ and TNF-α cytokines, and specifically kill DLL3 positive tumor cells. We have established a solid tumor model with heterogeneous antigen expression. CAR-T cells can effectively inhibit the growth of tumors with positive DLL3 expression in vivo, but the inhibition on tumors with heterogeneous antigens is not obvious. Blocking CD47 can promote phagocytosis of tumor cells by macrophages. Western blot analysis revealed the presence of CD47 blocking protein CV1-Fc in the supernatant of secreted CAR-T cells, which can effectively promote the phagocytic effect of macrophages; Armored CAR-T cells have a better anti-tumor effect in antigen heterogeneous tumor model in vivo, delays tumor progression, and promotes the aggregation of M1 type macrophages. Conclusions: CAR-T cells that specifically target DLL3 can effectively kill antigen-positive tumor cells in vivo and in vitro. Blocking CD47 can promote the non-specific anti-tumor effect of macrophages. CAR-T cells secreting CD47 blocking protein have dual anti-tumor effects, not only killing antigen-positive tumor cells, but also recruit and activate macrophages to exert phagocytosis, and have better anti-tumor effects in antigenic heterogeneous solid tumors.
Gilteritinib or venetoclax in relapsed or refractory <i>FLT3</i><sup>mut</sup> acute myeloid leukemia.
Authors: Graeme Murray, Ian Michael Bouligny, Tilak Patel, Michael Doyel, Josh Boron, Valerie Tran, Juhi Gor, Yiwei Hang, Thuy Ho, Kyle Zacholski, Chad Michael Venn, Yanal Mufeed Alnimer, Nolan Wages, Steven Grant, Keri Renee Maher
Journal: Journal of Clinical Oncology (2023)

e19046 Background: FLT3 mutations in AML are associated with high relapse rates and shorter survival compared to FLT3 wild-type. After intensive chemotherapy (IC) failure, clinicians can choose between several salvage regimens; however, the optimal therapy sequence remains unclear. This study compares two salvage therapies: gilteritinib or venetoclax and a hypomethylating agent (HMA; decitabine or azacitidine). Methods: We retrospectively analyzed 129 patients with AML and mutated FLT3-ITD or FLT3-TKD. We identified those that failed first-line IC (CPX-351 or conventional 7+3 with or without midostaurin) and received salvage. We compared patients treated with gilteritinib or venetoclax + HMA as the next line of therapy from January 1, 2018 to January 1, 2022 at VCU Massey Cancer Center. To reduce confounding, no patient in the venetoclax group received gilteritinib in a subsequent line of therapy. We recorded baseline disease characteristics, genetic risk by ELN 2022, induction regimens, response, and survival. We used Fisher’s exact test for nominal data and Mann-Whitney for ordinal data. We analyzed survival by the Kaplan-Meier method and compared groups with the log-rank test. Results: We identified 129 patients with FLT3-ITD or FLT3-TKD mutated AML and analyzed them over 228 treatment phases. In the front-line setting, 89 (68.9%) patients received IC; 55 (61.8%) received salvage therapy for relapsed or refractory disease, and 16 received either gilteritnib (N=6) or venetoclax-based (N=10) salvage. The median age of the gilteritinib cohort was significantly younger ( p = 0.007), but there were no differences between groups with respect to ELN 2022 adverse risk ( p = 0.633) or between ECOG ( p = 0.700) or Charlson Comorbidity Index scores ( p = 0.104). The composite complete remission (CCR; CR + CRi) rate of the gilteritinib cohort was 20.0%, compared to 60.0% for the venetoclax cohort ( p = 0.282). No patient in the gilteritinib cohort achieved MRD negativity. Among responders in the venetoclax cohort, MRD negativity was 75.0% ( p = 0.400). The median overall survival in the gilteritinib cohort was 3.9 months — significantly shorter than 7.8 months for the venetoclax cohort ( p = 0.048). Conclusions: Venetoclax + HMA appears superior to gilteritinib for subsequent therapy after IC failure in FLT3 mut AML, despite the gilteritinib cohort being significantly younger. The limitations of this study include its retrospective nature — prospective trials are needed to confirm these findings. [Table: see text]